Trimethyltin stimulates protein kinase C translocation through receptor-mediated phospholipase C activation in PC12 cells.
Trimethyltin (TMT) is a potent neurotoxic compound that initiates a delayed neuronal cell death. Previously we have shown that TMT-induced cytotoxicity is associated with protein kinase C (PKC) translocation and activation. The present study investigates the mechanism underlying TMT-stimulated PKC translocation in PC12 cells. TMT exposure led to a rapid increase in intracellular levels of inositol 1,4,5-trisphosphate (IP3), a product of phospholipase C (PLC). This was significantly decreased by pretreating cells with antagonists to either the cholinergic muscarinic receptor (atropine) or the glutamatergic metabotropic receptor [(+)-alpha-methyl-4-carboxyphenylglycine; (+)-MCPG]. Furthermore, the rise in IP3 level was blocked by pretreating cells with a PLC inhibitor (U-73122) or by a combination of atropine and (+)-MCPG. This pretreatment also significantly decreased TMT-stimulated PKC translocation, indicating that TMT-mediated PKC translocation was related to PLC activation, presumably through formation of diacylglycerol, an endogenous activator of PKC and product of PLC. It is interesting that atropine and (+)-MCPG did not provide protection against TMT-induced cytotoxicity in these cells. However, these data suggest that TMT causes the release of cellular constituents that activate G protein-coupled receptors, ultimately leading to PKC translocation.
Kane
M D
MD
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-1334, USA.
Yang
C W
CW
Gunasekar
P G
PG
Isom
G E
GE
D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation; D004789:Enzyme Activation; D004963:Estrenes / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D018727:Muscarinic Antagonists / Q000494:pharmacology; D016716:PC12 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D014298:Trimethyltin Compounds / Q000494:pharmacology*
D001565:Benzoates; D004963:Estrenes; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D011760:Pyrrolidinones; D018094:Receptors, Metabotropic Glutamate; D014298:Trimethyltin Compounds; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C079694:alpha-methyl-4-carboxyphenylglycine; C046488:trimethyltin; D001285:Atropine; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D005998:Glycine